Estrogen (E) affects both reproductive and non-reproductive functions, which are mainly mediated by the estrogen receptor (ER). Two ER isoforms, alpha and beta, share high structural homology, but display diverse transcriptional activities in response to E. In the presence of E, ligand-bound ER undergoes a rapid degradation through the ubiquitin-proteasome pathway, and this ER degradation tightly couples with its transcriptional activity. In addition, without E, ER can also be activated by cAMP-dependent protein kinase (PKA), and this E-independent ER activation may play an important role in the neuroendocrine system. Therefore, my long-term research objective is to elucidate the mechanisms by which PKA activates ER and the relevance to both physiology and disease. The interim goal for the current proposal will concentrate on understanding how the two ER isoforms can respond differently to the stimulation of forskolin (FSK) that activates PKA. Two specific aims will be examined: (1) identify specific region(s) residing in the rat ER alpha that mediate the FSK-induced ER activation; (2) test whether the specific FSK-responsive region(s) on rat ER alpha are required for maintaining ER alpha from degradation by the ubiquitin-proteasome pathway. The results of these studies should increase our understanding the molecular mechanisms for the E-independent activation of ER, and how this activation is linked to degradation.